Inflammatory diseases are often caused by inappropriate responses of effector CD4 T cells (Teff). Th1 and Th17 Teff are recognized to drive a variety of immune pathologies, including Inflammatory Bowel Disease (IBD) and Multiple Sclerosis (MS). Regulatory T cells (Treg), in contrast, suppress Teff to protect from disease. A key therapeutic objective in efforts to shift the immunologic balance towards tolerance, therefore, is to selectively inhibit Teff and promote Treg. We show here that Teff and Treg utilize fundamentally different metabolic programs and propose that identifying specific requirements of each subset will provide a new approach to selectively modulate CD4 T cells in inflammatory disease. We have found Th1 and Th17 cells have high expression of the glucose transporter Glut1, and Th17 cells in particular have increased Pyruvate Dehydrogenase Kinase 1 (PDHK1), an enrichment of glycolytic intermediates up to Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH), and elevated rates of glycolytic flux to lactate. Treg, in contrast, have low expression of Glut1 and PDHK1, limited glycolytic flux, and are instead enriched for mitochondrial oxidative gene expression and metabolites. Importantly, our analysis of T cell specific Glut1 conditional deletion or targeting of PDHK1 showed that a glycolytic program is selectively required for Teff function in vivo. Here we propose to test additional metabolic events that were identified by high- resolution metabolomics mass spectrometry as selectively regulated in Teff and that may provide vulnerabilities for Th1 and Th17. The regulation and requirements of Treg metabolism, in contrast, have been poorly understood. However, our data show that the transcription factor FoxP3 promotes Treg oxidative metabolism and suppresses the Phosphoinositide-3-kinase (PI3K)/Akt/mTOR pathway to lower Glut1 expression and glycolysis. Surprisingly, high rates of glycolysis reduced Treg suppressive capacity, as we found Glut1 transgenic Treg are functionally impaired and could not fully protect from IBD. Based on the distinct metabolic requirements of Teff and Treg, we hypothesize that key glucose-dependent metabolites are selectively essential for Teff while glycolysis is a Treg vulnerability that FoxP3 restrains to optimize suppressive capacity. To test this model we will: (1) Identify and characterize metabolites and metabolic pathways selectively required for Teff specification and function; (2) Determine how FoxP3 regulates metabolism and the role of glycolysis in Treg expansion and protection from IBD; (3) Establish how inhibition of glycolysis alters the Teff and Treg balance in a model of MS using selective PDHK1 inhibitors and targeting of Teff metabolic vulnerabilities. These studies will establish specific and selective metabolic demands of Teff and Treg physiology and identify pathways to modulate the Teff and Treg balance in inflammatory diseases.